Abstract
It is generally accepted that the foremost mechanism for the buffering of K+ from the extracellular space ([K+]o) in the brain is “K+ spatial buffering.” This is the process by which glial cells dissipate local K+ gradients by transferring K+ ions from areas of high to low [K+]o. These glial K+ fluxes are mediated mainly by inwardly rectifying K+ (Kir) channels. The K+ spatial buffering hypothesis has been tested and confirmed in the retina, in which is has been termed as “K+ siphoning”. In Müller cells, the primary glial cells of the retina, Kir channels are distributed in a highly non-uniform manner, exhibiting high concentrations in membrane domains facing the vitreous humor (endfeet) and in proximity to the blood vessels (perivascular processes). Such non-uniform distribution of Kir channels facilitates directed K+ fluxes in the retina from the synaptic plexiform layers to the vitreous humor and blood vessels. Recent molecular and electrophysiological studies in Müller cells have revealed a high degree of complexity in terms of Kir channel subunit composition, mechanisms of subcellular localization, and regulation. How such complexity fits into their proposed role in buffering [K+]o in retina is the main topic of this article.
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Schousboe A. (2003) Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission. Neurochem. Res. 28, 347–352.
Hatten M.E. (2002) New directions in neuronal migration. Science 297, 1660–1663.
Araque A., Carmignoto G., and Haydon P.G. (2001) Dynamic signaling between astrocytes and neurons. Annu. Rev. Physiol. 63, 795–813.
Nicholson C., Chen K.C., Hrabetova S., Tao L. (2002) Diffusion of molecules in brain extracellular space: theory and experiment. Prog. Brain Res. 125, 129–154.
Coles J.A. and Poulain D.A. (1991) Extracellular K+ in the supraoptic nucleus of the rat during reflex bursting activity by oxytocin neurones. J. Physiol. 439, 383–409.
Amedee T., Robert A., and Coles J.A. (1997) Potassium homeostasis and glial energy metabolism. Glia 21, 46–55.
Orkand R.K., Nicholls J.G., and Kuffler S.W. (1966) Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J. Neurophysiol. 29, 788–806.
Gardner-Medwin A.R. (1983) A study of the mechanisms by which potassium moves through brain tissue in the rat. J. Physiol. 335, 353–374.
Gardner-Medwin A.R. and Nicholson C. (1983) Changes of extracellular potassium activity induced by electric current through brain tissue in the rat. J. Physiol. 335, 375–392.
Karwoski C.J., Lu H.K., and Newman E.A. (1989) Spatial buffering of light-evoked potassium increases by retinal Müller (glial) cells. Science 244, 578–580.
Sontheimer. (1994) Voltage-dependent ion channels in glial cells. Glia 11, 156–172.
Adrian R.H. (1969) Rectification in muscle membrane. Prog. Biophys. Mol. Biol. 19, 339–369.
Hagiwara S. and Jaffe L.A. (1979) Electrical properties of egg cell membranes. Annu. Rev. Biophys. Bioeng. 8, 385–416.
Doupnik C.A., Davidson N., and Lester H.A. (1995) The inward rectifier potassium channel family. Curr. Opin. Neurobiol. 5, 268–277.
Reimann F. and Ashcroft F.M. (1999) Inwardly rectifying potassium channels. Curr. Opin. Cell Biol. 11, 503–508.
Yi B.A., Minor D.L., Jr., Lin Y.F., Jan Y.N., and Jan L.Y. (2001) Controlling potassium channel activities: Interplay between the membrane and intracellular factors. Proc. Natl. Acad. Sci. USA 98, 11,016–11,023.
Stanfield P.R., Nakajima S., and Nakajima Y. (2002) Constitutively active and G-protein coupled inward rectifier K+ channels: Kir2.0 and Kir3.0. Rev. Physiol. Biochem. Pharmacol. 145, 47–179.
Isomoto S., Kondo C., and Kurachi Y. (1997) Inwardly rectifying potassium channels: their molecular heterogeneity and function. Jpn. J. Physiol. 47, 11–39.
Nichols C.G. and Lopatin A.N. (1997) Inward rectifier potassium channels. Annu. Rev. Physiol. 59, 171–191.
Ruppersberg J.P. (2000) Intracellular regulation of inward rectifier K+ channels. Pflugers Arch. 441, 1–11.
Dascal N. (1997) Signalling via the G protein-activated K+ channels. Cell Signal 9, 551–573.
Mark M.D. and Herlitze S. (2000) G-protein mediated gating of inward-rectifier K+ channels. Eur. J. Biochem. 267, 5830–5836.
Aguilar-Bryan L. and Bryan J. (1999) Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr. Rev. 20, 101–135.
Suzuki Y., Yasuoka Y., Shimohama T., Nishikitani M., Nakamura N., et al. (2003) Expression of the K+ channel Kir7.1 in the developing rat kidney: Role in K+ excretion. Kidney Int. 63, 969–975.
Kohda Y., Ding W., Phan E., Housini I., Wang J., et al. (1998) Localization of the ROMK potassium channel to the apical membrane of distal nephron in rat kidney. Kidney Int 54, 1214–1223.
Xu J.Z., Hall A.E., Peterson L.N., Bienkowaski M.J., Eessalu T.E., Hebert S.C. (1997) Localization of the ROMK protein on apical membranes of rat kidney nephron segments. Am. J. Physiol. 273, F739-F748.
Derst C., Hirsch J.R., Preisig-Müller R., Wischmeyer E., Karschin A., et al. (2001) Cellular localization of the potassium channel Kir7.1 in guinea pig and human kidney. Kidney Int. 59, 2197–2205.
Ookata K., Tojo A., Suzuki Y., Nakamura N., Kimura K., et al. (2000) Localization of inward rectifier potassium channel Kir7.1 in the basolateral membrane of distal nephron and collecting duct. J. Am. Soc. Nephrol. 11, 1987–1994.
Krapivinsky G., Medina I., Eng L., Krapivinsky L., Yang Y., and Clapham D. E. (1998) A novel inward rectifier K+ channel with unique pore properties. Neuron 20, 995–1005.
Nakamura N., Suzuki Y., Sakuta H., Ookata K., Kawahara K., and Hirose S. (1999) Inwardly rectifying K+ channel Kir7.1 is highly expressed in thyroid follicular cells, intestinal epithelial cells and choroid plexus epithelial cells: implication for a functional coupling with Na+, K+ ATPase. Biochem. J. 342, 329–336.
Doring F., Derst C., Wischmeyer E., Karschin C., Schneggenburger R., et al. (1998) The epithelial inward rectifier channel Kir7.1 displays unusual K+ permeation properties. J. Neurosci. 18, 8625–8636.
Shimura M., Yuan Y., Chang J.T., Zhang S., Campochiaro P.A., et al. (2001) Expression and permeation properties of the K+ channel Kir7.1 in the retinal pigment epithelium. J. Physiol. 531, 329–346.
Kusaka S., Inanobe A., Fujita A., Makino Y., Tanemoto M., et al. (2001) Functional Kir7.1 channels localized at the root of apical processes in rat retinal pigment epithelium. J. Physiol. 531, 27–36.
Poopalasundaram S., Knott C., Shamotienko O.G., Foran P.G., Dolly J.O., et al. (2000) Glial heterogeneity in expression of the inwardly rectifying K+ channel, Kir4.1, in adult rat CNS. Glia 30, 362–372.
Li L., Head V., and Timpe L.C. (2001) Identification of an inward rectifier potassium channel gene expressed in mouse cortical astrocytes. Glia 33, 57–71.
Higashi K., Fujita A., Inanobe A., Tanemoto M., Doi K., et al. (2001) An inwardly rectifying K+ channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am. J. Physiol. Cell Physiol. 281, C922-C931.
Stonehouse A.H., Pringle J.H., Norman R.I., Stanfield P.R., Conley E.C., and Brammar W.J. (1999) Characterisation of Kir2.0 proteins in the rat cerebellum and hippocampus by polyclonal antibodies [In Process Citation]. Histochem. Cell Biol. 112, 457–465.
Leonoudakis D., Mailliard W., Wingerd K., Clegg D., and Vandenberg C. (2000) Inward rectifier potassium channel Kir2.2 is associated with synapse- associated protein SAP97. J. Cell Sci. 114, 987–998.
Nagelhus E., Horio Y., Inanobe A., Fujita A., Haug F., et al. (1999) Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Müller cells is mediated by coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26, 47–54.
Kofuji P., Biedermann B., Siddharthan V., Raap M., Iandiev I., et al. (2002) Kir potassium channel subnit expression in retinal glial cells: implications for spatial potassium buffering. Glia 39, 292–303.
Ishii M., Fujita A., Iwai K., Kusaka S., Higashi K., et al. (2003) Differential expression and distribution of Kir5.1 and Kir4.1 inwardly rectifying K+ channels in retina. Am. J. Physiol. Cell Physiol. 285, C260-C267.
Kubo Y., Baldwin T.J., Jan Y.N., and Jan L.Y. (1993) Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature 362, 127–133.
Zhou H., Tate S.S., and Palmer L.G. (1994) Primary structure and functional properties of an epithelial K channel. Am. J. Physiol. 266, C809-C824.
Lagrutta A.A., Bond C.T., Xia X.M., Pessia M., Tucker S., and Adelman J.P. (1996) Inward rectifier potassium channels. Cloning, expression and structure-function studies. Jpn. Heart. J. 37, 651–660.
Tanemoto M., Kittaka N., Inanobe A., Kurachi Y. (2000) In vivo formation of a proton-sensitive K+ channel by heteromeric subunit assembly of Kir5.1 with Kir4.1. J. Physiol. 525 Pt 3, 587–592.
Cui N., Giwa L.R., Xu H., Rojas A., Abdulkadir L., and Jiang C. (2001) Modulation of the heteromeric Kir4.1-Kir5.1 channels by P(CO(2)) at physiological levels. J. Cell Physiol. 189, 229–236.
Raab-Graham K.F. and Vandenberg C.A. (1998) Tetrameric subunit structure of the native brain inwardly rectifying potassium channel Kir 2.2. J. Biol. Chem. 273, 19,699–19,707.
Preisig-Müller R., Schlichthorl G., Goerge T., Heinen S., Bruggemann A., et al. (2002) Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen’s syndrome. Proc. Natl. Acad. Sci. USA 99, 7774–7779.
Tucker S.J., Imbrici P., Salvatore L., D’Adamo M.C., and Pessia M. (2000) pH dependence of the inwardly rectifying potassium channel, Kir5.1, and localization in renal tubular epithelia. J. Biol. Chem. 275, 16,404–16,407.
Xu H., Cui N., Yang Z., Qu Z., and Jiang C. (2000) Modulation of Kir4.1 and Kir5.1 by hypercapnia and intracellular acidosis. J. Physiol. 524 Pt 3, 725–735.
Matthias K., Kirchhoff F., Seifert G., Huttmann K., Matyash M., et al. (2003) Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus. J. Neurosci. 23, 1750–1758.
Steinhauser C., Berger T., Frotscher M., and Kettenmann H. (1992) Heterogeneity in the membrane current pattern of identified glial cells in the hippocampal slice. Eur. J. Neurosci. 4, 472–484.
Newman E. and Reichenbach A. (1996) The Müller cell: a functional element of the retina. Trends Neurosci. 19, 307–312.
Newman E. (1996) Regulation of extracellular K+ and pH by polarized ion fluxes in glial cells: the retinal Müller cell. The Neuroscientist 2, 109–117.
Brew H., Gray P., Mobbs P., and Attwell D. (1986) Endfeet of retinal glial cells have higher densities of ion channels that mediate K+ buffering. Nature 324, 466–468.
Newman E. (1993) Inward-rectifying potassium channels in retinal glial (Müller) cells. J. Neurosci 13, 3333–3345.
Solessio E., Linn D.M., Perlman I., and Lasater E.M. (2000) Characterization with barium of potassium currents in turtle retinal Müller cells. J. Neurophysiol. 83, 418–430.
Reichelt W., Müller T., Pastor A., Pannicke T., Orkand P.M., et al. (1993) Patch-clamp recording from Müller (glial) cell endfeet in the intact isolated retina and acutely isolated Müller cells of mouse and guinea-pig. Neuroscience 57, 599–613.
Chao T., Grosche J., Friedrich K., Biedermann B., Francke M., et al. (1997) Comparative studies on mammalian Müller (retinal glial) cells. J. Neurocytol. 26, 439–454.
Felmy F., Pannicke T., Richt J.A., Reichenbach A., and Guenther E. (2001) Electrophysiological properties of rat retinal Müller (glial) cells in postnatally developing and in pathologically altered retinae. Glia 34, 190–199.
Pannicke T., Bringmann A., and Reichenbach A. (2002) Electrophysiological characterization of retinal Müller glial cells from mouse during postnatal development: comparison with rabbit cells. Glia 38, 268–272.
Kusaka S. and Puro D. (1997) Intracellular ATP activates inwardly rectifying K+ channels in human and monkey retinal Müller (glial) cells. J. Physiol. (Lond) 500, 593–604.
Newman E.A. (1984) Regional specialization of retinal glial cell membrane. Nature 309, 155–157.
Newman E.A. (1987) Distribution of potassium conductance in mammalian Müller (glial) cells: a comparative study. J. Neurosci. 7, 2423–2432.
Newman E.A., Frambach D.A., and Odette L.L. (1984) Control of extracellular potassium levels by retinal glial cell K+ siphoning. Science 225, 1174–1175.
Ishii M., Horio Y., Tada Y., Hibino H., Inanobe A., et al. (1997) Expression and clustered distribution of an inwardly rectifying potassium channel, KAB-2/Kir4.1, on mammalian retinal Müller cell membrane: their regulation by insulin and laminin signals. J. Neurosci. 17, 7725–7735.
Tada Y., Horio Y., and Kurachi Y. (1998) Inwardly rectifying K+ channel in retinal Müller cells: comparison with the KAB-2/Kir4.1 channel expressed in HEK293T cells. Jpn. J. Physiol. 48, 71–80.
Kofuji P., Ceelen P., Zahs K.R., Surbeck L.W., Lester H.A., and Newman E.A. (2000) Genetic inactivation of an inwardly rectifying potassium channel (Kir4.1 subunit) in mice: phenotypic impact in retina. J. Neurosci. 20, 5733–5740.
Sheng M. and Sala C. (2001) PDZ domains and the organization of supramolecular complexes. Annu. Rev. Neurosci. 24, 1–29.
Sheng M. and Wyszynsky M. (1997) Ion channel targeting in neurons. BioEssays 19, 847–853.
Horio Y., Hibino H., Inanobe A., Yamada M., Ishii M., et al. (1997) Clustering and enhanced activity of an inwardly rectifying potassium channel, Kir4.1, by an anchoring protein, PSD-95/SAP90. J. Biol. Chem. 272, 12,885–12,888.
Neely J.D., Amiry-Moghaddam M., Ottersen O.P., Froehner S.C., Agre P., and Adams M.E. (2001) Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proc. Natl. Acad. Sci. USA 98, 14,108–14,113.
Amiry-Moghaddam M., Otsuka T., Hurn P.D., Traystman R.J., Haug F.M., et al. (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc. Natl. Acad. Sci. USA 100, 2106–2111.
Blake D.J., Hawkes R., Benson M.A., and Beesley P.W. (1999) Different dystrophin-like complexes are expressed in neurons and glia. J. Cell Biol. 147, 645–658.
Claudepierre T., Mornet D., Pannicke T., Forster V., Dalloz C., et al. (2000) Expression of Dp71 in Müller glial cells: a comparison with utrophin- and dystrophin-associated proteins. Investig. Ophthalmol. Vis. Sci. 41, 294–304.
Anderson J.L., Head S.I., Rae C., and Morley J.W. (2002) Brain function in Duchenne muscular dystrophy. Brain 125, 4–13.
Pillers D.A. (1999) Dystrophin and the retina. Mol. Genet. Metab. 68, 304–309.
Dalloz C., Claudepierre T., Rodius F., Mornet D., Sahel J., and Rendon A. (2001) Differential distribution of the members of the dystrophin glycoprotein complex in mouse retina: effect of the mdx (3Cv) mutation. Mol. Cell Neurosci. 17, 908–920.
Howard P.L., Dally G.Y., Wong M.H., Ho A., Weleber R.G., et al. (1998) Localization of dystrophin isoform Dp71 to the inner limiting membrane of the retina suggests a unique functional contribution of Dp71 in the retina. Hum. Mol. Genet. 7, 1385–1391.
Pillers D.A., Weleber R.G., Green D.G., Rash S.M., Dally G.Y., et al. (1999) Effects of dystrophin isoforms on signal transduction through neural retina: genotype-phenotype analysis of duchenne muscular dystrophy mouse mutants. Mol. Genet. Metab. 66, 100–110.
Cox G.A., Phelps S.F., Chapman V.M., and Chamberlain J.S. (1993) New mdx mutation disrupts expression of muscle and nonmuscle isoforms of dystrophin. Nat. Genet. 4, 87–93.
Connors N.C. and Kofuji P. (2002) Dystrophin Dp71 is critical for the clustered localization of potassium channels in retinal glial cells. J. Neurosci. 22, 4321–4327.
Claudepierre T., Dalloz C., Mornet D., Matsumura K., Sahel J., and Rendon A. (2000) Characterization of the intermolecular associations of the dystrophin-associated glycoprotein complex in retinal Müller glial cells. J. Cell Sci. 113, Pt 19, 3409–3417.
Rando T.A. (2001) The dystrophin-glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies. Muscle Nerve 24, 1575–1594.
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Kofuji, P., Connors, N.C. Molecular substrates of potassium spatial buffering in glial cells. Mol Neurobiol 28, 195–208 (2003). https://doi.org/10.1385/MN:28:2:195
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DOI: https://doi.org/10.1385/MN:28:2:195